Prolyl endopeptidase, a serine protease, plays an important role in the degradation of biologically active peptides such as vasopressin, oxytocin, angiotensins I and II, substance P, bradykinin, neurotensin, etc. Prolyl endopeptidase hydrolyzes these peptides and regulates their biological activities. D. De Wied and coworkers previously suggested and recently gave some evidence that vasopressin was involved in the process of learning and memory of animals..sup.1-4 In addition, the Nippon Roche group found an anti-amnestic agent aniracetam to inhibit PED..sup.5 T Yoshimoto (Nagasaki Univ.) synthesized specific PED inhibitors such as Z-Gly-Pro-CH.sub.2 Cl, Z-Pro-prolinal and Z-Val-prolinal based on the specificity of substrate for this enzyme and demonstrated correlation between their anti-amnestic activity in rats and PED inhibitory activity..sup.6 H Kaneto, et al. also confirmed anti-amnestic activity of vasopressin and the above synthetic PED inhibitors using several mouse models..sup.7
U.S. Pat. Nos. 4,857,537, 4,857,524, 4,826,870, 4,810,721, 4,772,587, 4,757,083, 4,743,616, and 4,701,465 relate to the synthetic production of compounds which are PED inhibitors.
Taking into consideration the above information, PED inhibitor screening was initiated by the present inventors with an intention to discover new anti-amnestic and/or anti-dementia compounds from microbial products.